rs2303995

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004519.4(KCNQ3):c.1241A>G(p.Glu414Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,190 control chromosomes in the GnomAD database, including 1,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 134 hom., cov: 33)

Exomes 𝑓: 0.027 ( 1213 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.49

Publications

21 publications found

Variant links:

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 Gene-Disease associations (from GenCC):

seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign neonatal seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017500818).

BP6

Variant 8-132163489-T-C is Benign according to our data. Variant chr8-132163489-T-C is described in ClinVar as Benign. ClinVar VariationId is 21409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4 link	c.1241A>G	p.Glu414Gly	missense_variant	Exon 9 of 15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 link	c.1241A>G	p.Glu414Gly	missense_variant	Exon 9 of 15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3752

AN:

152188

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0354

AC:

8886

AN:

251066

AF XY:

0.0338

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.0412

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.0371

Gnomad NFE exome

AF:

0.0224

Gnomad OTH exome

AF:

0.0276

GnomAD4 exome

AF:

0.0273

AC:

39844

AN:

1458882

Hom.:

1213

Cov.:

AF XY:

0.0270

AC XY:

19573

AN XY:

726072

show subpopulations

African (AFR)

AF:

0.00305

AC:

102

AN:

33444

American (AMR)

AF:

0.0396

AC:

1770

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

667

AN:

26110

East Asian (EAS)

AF:

0.200

AC:

7940

AN:

39634

South Asian (SAS)

AF:

0.0169

AC:

1461

AN:

86200

European-Finnish (FIN)

AF:

0.0365

AC:

1947

AN:

53392

Middle Eastern (MID)

AF:

0.00729

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0219

AC:

24304

AN:

1109340

Other (OTH)

AF:

0.0267

AC:

1611

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1750

3501

5251

7002

8752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

980

1960

2940

3920

4900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0246

AC:

3747

AN:

152308

Hom.:

134

Cov.:

AF XY:

0.0267

AC XY:

1985

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00476

AC:

198

AN:

41576

American (AMR)

AF:

0.0254

AC:

388

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3470

East Asian (EAS)

AF:

0.175

AC:

904

AN:

5178

South Asian (SAS)

AF:

0.0238

AC:

115

AN:

4824

European-Finnish (FIN)

AF:

0.0361

AC:

383

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1642

AN:

68020

Other (OTH)

AF:

0.0194

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

177

354

532

709

886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0265

Hom.:

314

Bravo

AF:

0.0238

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0210

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0224

AC:

193

ExAC

AF:

0.0340

AC:

4126

Asia WGS

AF:

0.0780

AC:

271

AN:

3478

EpiCase

AF:

0.0198

EpiControl

AF:

0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 17, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Seizures, benign familial neonatal, 2

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Apr 15, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Benign Neonatal Epilepsy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Benign neonatal seizures

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;.;.

Eigen

Benign

-0.024

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.55

T;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-0.48

PhyloP100

3.5

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.1

D;.;D;D;.

REVEL

Uncertain

0.35

Sift

Benign

0.032

D;.;D;D;.

Sift4G

Benign

0.14

T;T;T;T;.

Polyphen

0.12

B;.;.;B;.

Vest4

0.50

MPC

1.1

ClinPred

0.019

GERP RS

4.6

Varity_R

0.20

gMVP

0.70

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over